Xanthohumol induces paraptosis of leukemia cells through p38 mitogen activated protein kinase signaling pathway

Abstract

Xanthohumol as a natural polyphenol demonstrates an anticancer activity, but its underlying mechanism remains unclear. In this study, we showed that xanthohumol (XN) induces paraptosis of leukemia cells. The paraptosis is one cell death which is characterized by dilation of the endoplasmic reticulum and/or mitochondria. The results demonstrated that XN treatment significantly inhibited cell proliferation and triggered extensive cytoplasmic vacuolation of HL-60 leukemia cells, but it did not cause the cleavage of caspase-3 protein or apoptosis. In contrast, XN treatment resulted in LC3-II accumulation through blocking of autophagosome maturation. Interestingly, the induction of cytoplasmic vacuolization by XN is not associated with autophagy modulated by XN, therefore, XN-induced cell death of HL-60 leukemia cells is not the classical apoptotic cell death. Intriguingly, XN treatment triggered the dilatation of endoplasma reticulum (ER) and induced ER stress by upregulating C/EBP homologous protein and unfolded protein response regulator Grp78/Bip. Furthermore, XN treatment triggered p38 mitogen activated protein kinase and its specific inhibitor inhibited the paraptosis of HL-60 leukemia cells by XN. In conclusion, we for the first time demonstrated that XN treatment can induce paraptosis of leukemia cells through activation of p38 MAPK signaling.

Xanthohumol, a Prenylated Flavonoid from Hops, Induces Caspase-Dependent Degradation of Oncoprotein BCR-ABL in K562 Cells

“…Similarly, the autophagy inhibition was also observed in XN-treated A431 cell lines [42]. It has been reported that autophagy was inhibited by XN at the fusion of autophagosomes with lysosomes step in HL-60 cells [43]. Thus, autophagy was not the degradation way of XN-induced BCR-ABL degradation.…”

Chalcomoracin inhibits cell proliferation and increases sensitivity to radiotherapy in human non-small cell lung cancer cells via inducing endoplasmic reticulum stress-mediated paraptosis

“…It has been reported that cytoplasmic vacuolation induced by paraptosis is due to ER stress [ 16 , 21 ]. As shown in Fig.…”

“…Paraptosis is a type of nonapoptotic cell death characterized by dilation of the endoplasmic reticulum (ER) and/or mitochondria. Although the molecular mechanism of paraptosis is not well elucidated, studies have revealed that paraptosis is independent of the caspase signaling cascade and may involve activation of the mitogen-activated protein kinase (MAPK) pathway [ 15 , 16 ]. The ER stress markers Bip and Chop were found to be elevated in paraptosis [ 17 , 18 ].…”

Role of Zucchini and Its Distinctive Components in the Modulation of Degenerative Processes: Genotoxicity, Anti-Genotoxicity, Cytotoxicity and Apoptotic Effects

“…During apoptosis, intracellular contents are not released and potentially harmful inflammatory responses are prevented. Apoptotic cell death is characterized by a DNA fragmentation into 180–200 pb nucleosomal units [ 17 ] and at the molecular level the apoptotic way can also be monitored trough the Annexin V/PI assay [ 57 ]. The DNA fragmentation assay was only able to detect apoptosis in HL60 exposed to highest concentrations of “Light Green” zucchini epicarp.…”